The growing obesity epidemic in the US has heightened the importance of its primary prevention across all ages;however, prevention efforts generally focus upon community-based intervention studies in pediatric settings or clinical intervention studies among already overweight or obese adults. Obesity commonly develops during adulthood and necessitates an improved understanding of long- term strategies to prevent adult-onset obesity. The epidemiologic literature is limited regarding specific types or intensities of physical activity beyond total physical activity, as well as dietary patterns that may be associated with the development of obesity and long-term weight gain during middle and late adulthood. Therefore, this revised proposal responds to PA-06-256 (Exploratory/Developmental Clinical Research Grants in Obesity) and seeks to develop incident obesity as a new endpoint within two large existing prospective cohort studies of men and women. The Harvard Alumni Health Study includes 12,805 men aged e55 years who completed a baseline questionnaire in 1988 along with 10 years of follow-up, and the Women's Health Study consists of 39,876 women aged e45 years with baseline information in 1992 plus more than 12 years of follow-up for the development of obesity and long-term weight gain. In this proposal, we will carefully evaluate the roles of physical activity, physical inactivity, and diet in the prevention of adult-onset obesity and long-term weight gain in initially non- obese men and women. Our first primary aim will examine whether physical inactivity is associated with an increased risk of becoming obese or greater increases in body weight during long-term follow- up. We will also examine the type (e.g. walking and other common forms of exercise), frequency, and intensity (e.g. moderate, vigorous) of physical activity. Second, we will determine whether specific dietary factors (e.g. Western versus prudent dietary patterns, fruits and vegetables, fiber, carbohydrates, dairy products, and alcohol) are associated with an increased risk of becoming obese or greater increases in body weight. Finally, we will determine whether the above associations are modified by the presence or absence of intermediate clinical factors such as hypertension, diabetes, hypercholesterolemia, or parental history of obesity (available in men only). We have excellent power to assess our hypotheses to draw clinically meaningful conclusions regarding the role of different types and intensities of physical activity, sedentary behaviors, and dietary factors in the primary prevention of obesity. With the successful development of adult-onset obesity and long-term weight gain in these cohorts, we hope this proposal will lead to larger R01 grants with greater scope to examine additional aspects of physical activity, physical inactivity, diet, and related biomarkers and genetic factors to identify promising mechanisms and innovative approaches for the prevention of obesity in adults. PUBLIC HEALTH RELEVANCE: Project Narrative The growing obesity epidemic in the US has heightened the need to improve our understanding of how to prevent adult-onset obesity. We are responding to PA-06-256 (Exploratory/Developmental Clinical Research Grants in Obesity) to develop adult-onset obesity as a new endpoint in two large existing prospective cohort studies, the Harvard Alumni Health Study and the Women's Health Study. We will carefully evaluate the roles of physical activity, physical inactivity, and diet in the prevention of adult-onset obesity and long-term weight gain in initially non-obese middle-aged and older men and women. The clinically relevant results generated from this proposal will help establish obesity as a viable endpoint in these two large cohort studies and provide an opportunity to expand research to other mechanistically relevant biomarkers, genetic factors, and risk factors in the primary prevention of obesity.